title: Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigs.
abstract: Monodesmethyl cyamemazine and cyamemazine sulfoxide, the two main metabolites of the antipsychotic and anxiolytic phenothiazine cyamemazine, were investigated for their effects on the human ether-à-go-go related gene (hERG) channel expressed in HEK 293 cells and on native I(Na), I(Ca), I(to), I(sus) or I(K1) of human atrial myocytes. Additionally, cyamemazine metabolites were compared with terfenadine for their effects on the QT interval in anaesthetized guinea pigs. Monodesmethyl cyamemazine and cyamemazine sulfoxide reduced hERG current amplitude, with IC50 values of 0.70 and 1.53 microM, respectively. By contrast, at a concentration of 1 microM, cyamemazine metabolites failed to significantly affect I(Na), I(to), I(sus) or I(K1) current amplitudes. Cyamemazine sulfoxide had no effect on I(Ca) at 1 microM, while at this concentration, monodesmethyl cyamemazine only slightly (17%), albeit significantly, inhibited I(Ca) current. Finally, cyamemazine metabolites (5 mg kg(-1) i v.) were unable to significantly prolong QTc values in the guinea pig. Conversely, terfenadine (5 mg kg(-1) i.v.) significantly increased QTc values. In conclusion, cyamemazine metabolite concentrations required to inhibit hERG current substantially exceed those necessary to achieve therapeutic activity of the parent compound in humans. Moreover, cyamemazine metabolites, in contrast to terfenadine, do not delay cardiac repolarization in the anaesthetized guinea pig. These non-clinical findings explain the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use.
authors.affiliation: Zenas Technologies, New Orleans, LA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Crumb
authors.forename: Amine
authors.initials: A
authors.lastname: Benyamina
authors.forename: Christophe
authors.initials: C
authors.lastname: Arbus
authors.forename: George P
authors.initials: GP
authors.lastname: Thomas
authors.forename: Ricardo P
authors.initials: RP
authors.lastname: Garay
authors.forename: Ahcène
authors.initials: A
authors.lastname: Hameg
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000633:toxicity*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010640:Phenothiazines / Q000008:administration & dosage / Q000633:toxicity*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D003499:Cyclic S-Oxides; D051638:Ether-A-Go-Go Potassium Channels; D010640:Phenothiazines; D015221:Potassium Channels; D015222:Sodium Channels; C533908:cyamemazine sulfoxide; C533907:monodesmethyl cyamemazine